Ammonia and Chloramines

Anhydrous ammonia [ammonia (NH₃)] is a colorless gas that is lighter than air at room temperature. It has a very pungent odor which can be detected when the concentration of the gas is ≥5 parts per million (ppm).²¹ Anhydrous ammonia is the third most abundantly produced chemical in the world, and it has many household and industrial uses.²¹ Ammonia was first isolated in its pure gaseous form in 1790, and the first suspected inhalational poisoning was reported in 1841.⁷ Ammonia is transported under pressure as a liquid, and it can cause a hypothermic injury when it is decompressed to normal atmospheric pressure. Ammonia is used as a fertilizer, an explosive, and a chemical weapon.²¹ It is also used in the production of paper and pulp, in the refrigeration and petroleum industry, and in the production of dyes, plastics, and fibers.^8,16 Accidents and exposures involving ammonia are increasingly common, as this substance is a key intermediate in the illicit production of methamphetamine.¹¹

Because of its high water solubility, clinical manifestations of exposure to ammonia gas present immediately. People generally escape the exposure before becoming symptomatic, as the odor threshold of approximately 5 to 50 ppm is much lower than the irritant threshold of 400 ppm.^10,22 However, ammonia is associated with olfactory fatigue,²¹ so people may believe they have removed themselves from an exposure when they have not. Ocular injuries are associated with exposures to concentrations ≥700 ppm. Exposures to concentrations between 2500 and 4500 ppm can lead to death within 30 minutes, largely due to airway obstruction.^8,21 Concentrations of ammonia ≥5000 ppm are rapidly fatal.^7,10,22

The extent of injury depends upon the duration of exposure, depth of inhalation, gas concentration, and pH of the gas.^11,23 Interestingly, anhydrous ammonia itself is not caustic.²⁴ When it dissolves in water, such as in the mucous membranes, it forms ammonium hydroxide (NH₄OH), a strong base.^11,21 The dissociation of ammonium hydroxide into hydroxyl ions (see below) also damages tissues and causes liquefaction necrosis.^7,10

Ammonium hydroxide formation and its dissociation:

NH₃ + H₂O ↔ NH₄OH ↔ NH₄OH → NH₄⁺ + OH⁻

Injury to the mucosa leads to sloughing of the mucosal barrier, formation of cellular debris, edema, hemorrhage, and smooth-muscle contraction. Collectively, these effects of ammonia toxicity can precipitate airway obstruction. In one case report, injury after a massive exposure was so severe the patient required bilateral lung transplantation.¹⁰

Injuries occur first to the eyes, oropharynx, and upper respiratory tract, owing to ammonia’s high water solubility. After prolonged exposure to ammonia or after exposure to a high concentration of the gas, the lower respiratory tract is also injured.²⁴ Ocular injuries (or their sequelae) include conjunctivitis, ulceration, iritis, cataract formation, blepharospasm, and glaucoma. Ammonia also causes hypoxia when it displaces oxygen in the lower respiratory tract.

Chloramines (see below) are nitrogenous chlorinated compounds. They are very irritating gasses produced when household bleach reacts with ammonia. Symptoms due to exposure to chloramines are typically very mild and occur very quickly, allowing potential victims to escape. However, if there is prolonged exposure or exposure to a high concentration of the gas, the patient can have injuries typical of any highly water-soluble irritant.

Chloramine production:

3 NaOCl + 2 NH₃ ↔ NH₂Cl + NHCl₂ + 3 NaOH. B, NH₂Cl + H₂O ↔ HOCl + NH₃

Chlorine

Chlorine is a green-yellow gas with a very pungent odor that is twice as dense as air. It was discovered in the 1770s and soon became useful as a commercial agent.^17–18 Its odor can be detected at concentrations as low as 0.2 ppm.¹⁸ Its intermediate solubility in water promotes damage at all levels of the respiratory tract.²⁵ Exposures to chlorine concentrations greater than 430 ppm have resulted in death.¹⁷ Chlorine causes cellular injury by the generation of oxygen free radicals and oxidation of functional groups in cellular components.⁹

Chlorine has many uses. France and Germany used it as a chemical warfare agent during World War I. Today, people are exposed at home or during industrial accidents. Exposure at home can occur while chlorinating a pool or swimming. Chlorine gas is also produced when bleach containing hypochlorite is mixed with an acid. Industrial uses include water purification, textile and paper bleaching, chemical and plastic manufacturing, and disinfection.¹⁸

Chlorine gas directly damages the respiratory mucosa when it combines with water to form hypochlorous and hydrochloric acids (see below). Free radicals are formed which propagate an inflammatory response, leading to neutrophil recruitment and cytokine release. Epithelial cell necrosis and increased pulmonary microvascular permeability have been demonstrated in animal models.²⁶

Chlorine:

Cl₂ + H₂O → HCl + HOCl

The end result is edema and hemorrhage of the respiratory tract, with bronchiolar mucosal destruction and formation of exudate-filled alveoli. These responses predispose the respiratory tract to bacterial superinfection and ALI. Patients present with inflammation of the conjunctivae and upper respiratory tract, ALI, and respiratory failure. They develop bronchospasm, rales, a sore throat, cough, tachycardia, tachypnea, and hypoxia. Tachycardia is a result of pain, coughing, and hypoxia.

The value of nebulized sodium bicarbonate (NSB) to neutralize hydrochloric acid is debatable,⁹ but this therapeutic intervention likely has no adverse effects.²⁵ The use of NSB is based on the assumption that there is a benefit from neutralization of the acids formed after chlorine exposure.^15,27 The solution for nebulization is prepared by mixing 2 mL of 7.5% sodium bicarbonate with 2 mL of normal saline,¹⁵ or 3 mL of 8.4% sodium bicarbonate with 2 mL of normal saline.²⁷

Little data on the use of NSB exist. There are case reports describing rapid and successful improvement in patients after a single NSB treatment.^14–15 No adverse events were reported in a retrospective review of poison center data involving 86 patients treated with NSB.²⁷ Only 17 of the 86 patients required hospital admission. Among the admitted patients, mean hospital length of stay was 1.4 days. The timing and number of treatments and other adjunctive therapies varied among patients. Although unable to prove its efficacy, the authors concluded that NSB was potentially beneficial.²⁷ A double-blind study of ED patients concluded that NSB was useful for treating patients with reactive airway dysfunction syndrome (RADS) secondary to chlorine gas exposure.²⁸ Forty-four patients with RADS who were treated with corticosteroids and β₂-agonists were pseudorandomized to receive either NSB or a nebulized placebo. Patients were placed in either the control or treatment group based on an even/odd presentation system (patients numbered 1, 3, 5, etc. were placed into one group, while patients 2, 4, 6, etc. were placed in the other group). To be diagnosed with RADS in this series, patients without preceding disease had to develop pulmonary complaints within 24 hours of a single exposure and have symptoms persist for at least 3 months. The patients who received NSB had significantly higher FEV₁ values.²⁸

Phosgene

Phosgene (COCl₂ or carbonyl chloride) is a colorless gas that is more dense than air.²⁹ It was used as a chemical agent during World War I. Today, exposures occur during the synthesis of plastics and industrial materials, from decomposition of chlorinated hydrocarbons, or during the accidental heating of chlorofluorocarbons. The global consumption of phosgene was 5 million metric tons in 2006.³⁰ Concentrations above 500 ppm/min are associated with fatalities.³¹

Phosgene’s odor has been described as similar to that of freshly mown hay. Even with its low odor threshold of 0.4 to 1.5 ppm, people may not remove themselves from an exposure because of its pleasant smell and/or development of olfactory fatigue.³¹ These factors combined with its minimal acute irritant effects cause people to suffer prolonged exposures, permitting the gas to enter the lower airways and leading to development of ALI, since dose determines degree of damage.³¹

Phosgene damages the respiratory tract by denaturing proteins and irreversibly disrupting the structure of cellular membranes.³¹ It also promotes depletion of glutathione and other endogenous antioxidants.^30–31 Phosgene forms hydrochloric acid (HCl) when it reacts with water in mucous membranes.²⁹ These pathophysiologic effects result in pulmonary edema and hypoxia.³²

Symptoms may initially include minor upper respiratory tract irritation. Patients then enter a latent phase and may improve clinically but still have ongoing biochemical injury. This latent phase can last hours; its duration is inversely proportional to the inhaled dose.³¹ The latent period is followed by ALI and pulmonary edema.³¹ The smell of gas or irritative effects have no prognostic significance,^29,31 so cases of only moderate exposure to phosgene warrant further observation. Patients with a normal chest x-ray and without any signs or symptoms can be discharged after 8 hours of observation.³¹ Admitted patients who require endotracheal intubation should be treated with a protective ventilation strategy.³²

Multiple treatment strategies target the reduction of inflammation produced by phosgene.³¹ N-acetylcysteine (NAC), aminophylline, isoproterenol, ibuprofen, and corticosteroids have all been studied in animal models.^33–37 Sciuto et al. tested multiple interventions after exposing rabbits and mice to phosgene.³⁴ The rabbit model demonstrated improvement in multiple variables including decreased intratracheal pressure, increased cyclic adenosine monophosphate (cAMP) concentration in the lung tissue and decreased leukotriene formation after receiving aminophylline and intratracheal instillation of NAC and isoproterenol. The 12-hour survival rate was improved in mice exposed to phosgene after treatment with intraperitoneal ibuprofen, although survival at 24 hours was not affected.³⁴ Others suggest that NAC ameliorates injury by helping to avoid depletion of glutathione.^35–36 In a rabbit model, corticosteroids given 1 hour before exposure to phosgene prevented damage from leukotrienes and other lipoxygenase derived products. Survival was not studied.³³ In a porcine model, treatment with intravenous (IV) methylprednisolone or inhaled budesonide after exposure to phosgene failed to decrease mortality at 24 hours.³⁷ Borak and Diller suggested treating patients with methylprednisolone (250 mg IV) or NAC (20 mL of a 20% nebulized solution).³¹

Carbon Monoxide

CO is a colorless, odorless gas produced from the incomplete combustion of carbon-containing fuels.³⁸ Common sources of carbon monoxide include house fires, smoke inhalation, automobile exhaust, indoor heating systems and water heaters, forklifts, electric generators, and Zambonis. CO exposure is the leading cause of mortality from poisoning in the United States, accounting for an estimated 40,000 emergency department visits and 800 to 6000 deaths per year.^39–40 These numbers may be underestimates because of the nonspecific signs and symptoms of CO poisoning.⁴¹

CO binds hemoglobin, forming carboxyhemoglobin, with an affinity 200 times greater than that of oxygen.^{38,40,42–44} The high affinity of CO for hemoglobin interferes with the ability of hemoglobin to bind oxygen and also shifts the oxygen dissociation curve to the left, preventing release of oxygen from hemoglobin in tissues.^43,45–47 CO also binds to other heme-containing proteins.^44–45 CO also disrupts the electron transport chain by binding to cytochrome aa3.⁴⁷ By binding to myoglobin,⁴⁴ CO reduces oxygen availability in cardiac tissue.⁴⁰ CO also increases nitric oxide levels, causing vasodilatation which results in syncope.^40,47 Neurologic injury may be the result of reperfusion injury to the hypoxic tissue.⁴⁶

CO is called the “great imitator,” because patients present with nonspecific signs and symptoms including headache, fatigue, malaise, and influenza-like and gastroenteritis-like symptoms.⁴³ The brain and heart have higher oxygen requirements and are more severely affected by CO-induced cellular hypoxia⁴⁶; patients develop electrocardiographic (ECG) changes, chest pain, myocardial infarction,⁴³ syncope, and neurologic deficits.⁴⁰ Neurologic sequelae are divided into persistent neurologic sequelae (PNS) and delayed neurologic sequelae (DNS).⁴⁴ PNS occur at the time of exposure, whereas DNS begin 2 to 40 days after exposure. Fear of these sequelae is the rationale behind hyperbaric oxygen therapy (HBO).

PNS and DNS share the same psychoneurologic symptoms,⁴⁸ including aphasia, apraxia, apathy, disorientation, hallucinations, bradykinesia, rigidity, gait disturbances, and personality changes.⁴⁷ The incidence of DNS is unknown for two primary reasons: lack of a consistent definition⁴² and lack of validated neuropsychometric tests to screen for presence of the syndrome.⁴⁰ Current research is focused on finding biomarkers to assess risk for DNS.⁴⁹

Samples of either venous or arterial blood can be used to measure CO levels, because they correlate well in prospective studies.^40–41 A level greater than 2% in nonsmokers or 9% in smokers suggests exposure to exogenous CO.^39,41 Because patients are removed from the exposure and/or receive oxygen prior to the level being obtained, levels may be “falsely” low. Carboxyhemoglobin levels do not correlate well with the patient’s clinical presentation or degree of injury, particularly at higher levels.^41,44,47 Patients exposed to CO can have lactic acidosis.⁴⁰ Pulse oximeters report falsely elevated hemoglobin saturations, as these devices fail to differentiate between oxygenated hemoglobin and carboxyhemoglobin. Conversely, co-oximetry differentiates between oxyhemoglobin and carboxyhemoglobin. Newer handheld oximetry probes accurately detect carboxyhemoglobin. Low-density bilateral globus pallidus lesions have been reported on head computed tomography (CT). These lesions, which may resolve with time, often develop within a few hours after the injury,⁴⁷ but their appearance can be delayed for days.⁴⁰

Placing patients on 100% oxygen lowers the half-life of carboxyhemoglobin from 240 minutes on room air to 80 minutes. Hyperbaric oxygen (HBO) lowers the half-life to approximately 20 minutes.⁴⁰

The use of HBO is controversial.^44,50 Four prospective randomized trials have evaluated its use.^48,50–52 The studies differed with respect to inclusion criteria, outcomes, definition of DNS, and HBO protocols. Of the four, the Weaver et al.⁴⁸ and Scheinkestel et al.⁵⁰ studies were the only ones that were blinded via the use of sham HBO (chamber was turned “on” and made noise but was not pressurized). The Weaver study is the most methodologically rigorous and well controlled of all the trials but is not above criticism⁴⁰; it included patients with documented exposure to CO and also symptomatic patients thought to be exposed to CO.⁴⁸ Patients underwent three treatments within 24 hours; the first at 3 atmospheres absolute (ATA) and the others at 2 ATA. Pregnant patients, patients younger than 16 years of age, moribund patients, and anyone more than 24 hours from exposure were excluded. Weaver et al. concluded that HBO decreased the frequency of cognitive sequelae at 6 weeks and 12 months. The number needed to treat was 5 at 6 weeks.⁴⁸ In the Scheinkestel study, the hyperbaric group received HBO once daily at 2.8 ATA for 60 minutes for 3 to 6 days.⁵⁰ Except for children and pregnant women, any patient with CO poisoning, regardless of the severity or time since exposure, was included. Patients were assessed with many neuropsychiatric tests at the completion of hyperbaric treatment and 1 month later. All five cases of DNS occurred in the group that received HBO. Also, the normobaric group had fewer abnormal neuropsychiatric tests at the completion of therapy. The authors concluded that HBO did not offer a benefit and may have worsened some outcomes. However, only 46% of patients were followed up at 1 month, weakening the conclusions from this study.⁵⁰ Conversely, there was a 97% follow-up rate in the study by Weaver and coworkers.⁴⁸

Two other trials were randomized but not blinded.^51–52 Raphael et al.⁵² included 629 patients with accidental inhalation of CO who presented within 12 hours of exposure. Pregnant women were excluded. Patients were stratified on the basis of absence or presence of loss of consciousness (LOC), and treatment groups received one or two treatments with HBO. Follow up at 1 month was carried out using a self-assessment questionnaire. Raphael et al.⁵² concluded that HBO might offer some benefit in patients with LOC, but not in patients without LOC. The study by Thom and colleagues⁵¹ enrolled 60 patients who presented within 6 hours of exposure to CO. The subjects were randomized to receive either one session of HBO or normobaric oxygen. Patients with LOC or EKG changes were excluded. Patients receiving HBO had a lower incidence of DNS determined by testing immediately afterwards and at 1 month.⁵¹

Although controversy exists regarding the indications for HBO, we suggest using the enrollment criteria from the study by Weaver et al.,⁴⁸ because this study’s methods improved outcomes. Indications, therefore, include neurologic findings (altered mental status, coma, focal deficits, seizures), syncope, pregnancy with carboxyhemoglobin concentration above 15%, cardiovascular compromise (ischemia, infarction, dysrhythmia), metabolic acidosis, concentrations greater than 25% in nonpregnant patients, and extremes of age.⁴⁰ The only absolute contraindication is untreated pneumothorax, but relative contraindications include chronic obstructive pulmonary disease, fever, bowel obstruction, and significant upper respiratory tract infection.^40,53

The most common complication of HBO therapy is barotrauma; however, oxygen toxicity and seizures also have been reported.^40,48,50,53 While in the HBO chamber, the patient cannot receive defibrillation or electrical cardioversion. Also, the treatment team has limited access to the patient. Therefore some patients may be too unstable for HBO. In some cases, logistical challenges or the patient’s underlying instability may render the situation so dangerous or so complex that transport to a facility that offers HBO is unfeasible.

Cyanide

Cyanide is one of the most rapidly acting and lethal poisons in existence.⁵⁴ Its infamy stems from its use in mass killing by the Nazis during World War II and the mass suicide led by Jim Jones in the 1970s. Other sources of cyanide include food (pits of members of the genus Prunus), photographic developer solutions, electroplating solutions, rodenticides, artificial nail remover, and sodium nitroprusside metabolism. Inhalation of smoke from structural fires is the most common source of cyanide exposure in the United States and Western countries.^55–56 Hydrogen cyanide formation from the combustion of carbon- and nitrogen-based materials and abundant plastics, polymers, synthetic fibers, and wools in houses are major contributors.^54–55 Cyanide toxicity also should be suspected in the sudden collapse of a laboratory or industrial worker or an unexplained coma or severe acidosis following a suicide attempt.⁵⁷ The clinical effects of cyanide poisoning depend on the dose, duration, and route of exposure.⁵⁸

Cyanide binds to the ferric iron portion of cytochrome oxidase and inhibits it at the cytochrome a3 portion of the mitochondrial electron transport chain.^8,54,58–59 Binding of cyanide to cytochrome oxidase prevents mitochondria from using oxygen, thereby inhibiting aerobic metabolism.^55–56 Clinical manifestations reflect the failure of aerobic respiration.⁵⁸ The CNS and heart have high demands for oxygen and are the most susceptible organs to cyanide poisoning.⁵⁴ Transient increases in blood pressure, respiratory rate, and heart rate are followed by respiratory depression without cyanosis and cardiovascular collapse.⁵⁵ Patients may present with syncope, dilated pupils, or seizures.⁵⁹ Other presentations include headache, confusion, lethargy, agitation, and pulmonary edema. Unmetabolized cyanide has a bitter-almond-like odor and is excreted during breathing. However, 50% of the population cannot detect the odor.^55,58

Hallmark laboratory findings include metabolic acidosis with elevated circulating lactate concentration.⁵⁵ In smoke inhalation victims, blood lactate concentration above 10 mmol/L suggests cyanide toxicity.⁶⁰ In victims of cyanide poisoning, the oxygen content of venous blood is abnormally high due to inhibition of cellular oxygen utilization.^55,58 The arteriovenous oxygen saturation difference may be less than 10 mmHg, and “arterialization” of venous and capillary blood is responsible for the characteristic cherry-red complexion and bright red retinal veins seen on examination of cyanide poisoning victims.^55,58 Cyanide is an unstable molecule with a short half-life, and blood levels usually are not available from the laboratory in a timely enough fashion to be clinically useful.⁵⁹ As such, the diagnosis is difficult to make and requires a high level of suspicion.⁶¹

There are two specific cyanide treatments available in the United States.⁵⁴ The traditional kit available from Eli Lilly and Company contains amyl nitrite, sodium nitrite, and sodium thiosulfate. Amyl nitrite ampules are inhaled to produce a methemoglobinemia. Once IV access is established, sodium nitrite (300 mg) is given IV to induce a methemoglobinemia (methemoglobin concentration = 20%-30%). Cyanide preferentially binds to methemoglobin over hemoglobin, forming cyanomethemoglobin.⁶² Administration of nitrites can be detrimental, however, because of the complications associated with methemoglobinemia.⁵⁴ These complications include dyspnea, hypotension, acidosis, tachycardia, tachypnea, syncope, and CNS depression. Methemoglobinemia is a problem for patients who have been in a fire, as they may already have a significant carboxyhemoglobinemia^54,56; thus, deliberate induction of methemoglobinemia results in two hemoglobinopathies at once.⁶¹ Sodium thiosulfate acts as a substrate to convert cyanide to thiocyanate but has a comparatively delayed onset of action.⁶³ Adult dosing is 12.5 grams IV as a bolus or over half an hour.

Hydroxocobalamin is a precursor of vitamin B₁₂ and binds to cyanide to form cyanocobalamin (vitamin B₁₂), which is then renally excreted.⁶¹ Unlike the case with nitrites, hydroxocobalamin has few side effects. It is associated with temporary skin discoloration that can interfere with the accuracy of co-oximetry. A recent review recommends hydroxocobalamin (5 g IV) for empirical treatment of smoke inhalation victims suspected of having cyanide toxicity.⁶¹

Hydrogen Sulfide

Hydrogen sulfide is a colorless gas with a characteristic “rotten egg” odor.⁶⁴ It is a byproduct of human and animal waste and produced by the decay of organic material.⁶⁵ Its mechanism of toxicity is through competitive inhibition of the electron transport chain,^66–68 but it also is an irritant.^{65, 69}

Hydrogen sulfide’s odor is perceived at levels of 3 to 30 ppm,⁶⁵ with olfactory paralysis occurring at 100 to 150 ppm.^66–67 Patients present with complaints including headache, weakness, incoordination, cough, dyspnea, and gastrointestinal symptoms.⁶⁶ Cyanosis, pulmonary edema, cardiac dysrhythmias, and keratoconjunctivitis are present on examination.⁶⁶ If an exposed patient has coins (e.g., dimes or quarters) in his or her pockets during the period when hydrogen sulfide is present in the atmosphere, the coins undergo reaction with the gas and turn black.⁶⁷ Diagnosis is based on history, because a clinically useful laboratory test is not readily available.

There may be a role for nitrites and HBO in the treatment of hydrogen sulfide toxicity. The nitrite-induced methemoglobin has a high affinity for hydrogen sulfide and enables cytochrome oxidase to resume aerobic metabolism.⁶⁵ Case reports refer to the use of HBO, as it may enhance detoxification of hydrogen sulfide.^64,70 However, there is little supporting evidence for HBO, and its use cannot be recommended enthusiastically until further research is conducted.^64–6568